Osteoporosis is a major public health problem that affects more than 10 million people in the US and results in 1.5 million fractures annually. Intermittent administration of parathyroid hormone (PTH) is the most effective current treatment for osteoporosis. PTH improves bone mass and bone microarchitecture, increases bone strength, and reduces the risk for fractures. However, the molecular mechanism underlying the anabolic actions of PTH on bone formation remains poorly understood. Gene deletion studies showed that activating transcription factor 4 (ATF4) is a critical factor for bone formation. The findings from our preliminary studies strongly suggest that PTH controls osteoblast-specific gene expression and bone formation, at least in part, through ATF4. The long-term goal of this project is to understand how PTH signals regulate osteoblast activity in bone formation. Our hypotheses are: i) PTH activates ATF4 by promoting its phosphorylation and protein-protein interactions with Runx2, and ii) ATF4 mediates the anabolic actions of PTH on bone. To test these hypotheses, we will pursue the following Specific Aims: Aim 1. Determine the mechanism used by PTH to regulate ATF4 and Runx2 transcriptional activity. To accomplish this aim: i) we will identify the PTH responsive phosphorylation sites in ATF4 and assess the functional significance of PTH-induced phosphorylation in ATF4 in cultured cells;ii) We will define the regions/amino acid residues within ATF4 and Runx2 that mediate the ATF4-Runx2 interactions;and iii) we will determine whether PTH signals increase ATF4-Runx2 binding and if these interactions are necessary for PTH actions in osteoblasts in vitro. Aim 2. Establish whether the anabolic actions of PTH require ATF4. We will determine if ATF4 is required for the anabolic actions of PTH in vivo using the ATF4-deficient mice and transgenic mice overexpressing ATF4 in osteoblasts. Aim 3. Determine whether ATF4-Runx2 interactions are required for normal and PTH-induced bone formation in vivo. This project will explore a novel mechanism to explain the anabolic actions of PTH and define new potential therapeutic targets for improved treatment of osteoporosis and other metabolic bone diseases.